The strategy of using anti-tumour antibodies labelled with radioactive isotopes to target and eliminate tumour cells, known as radioimmunotherapy, is an old concept in cancer therapy, with a history marked by periods of both optimism and disappointment. The advent of hybridomas boosted the discovery of a large number of candidate mouse anti-tumour antibodies with potential use in radioimmunotherapy, but this optimism was tempered by the problem of the human anti-mouse monoclonal antibody response (HAMMA), which in some instances has been countered by the engineering of humanised mouse monoclonal antibodies. Genetic engineering has also provided the means to generate and select antibody variants to optimise affinity of the antibody for the target antigen. From this background, radioimmunotherapy is now an established mode of cancer therapy for lymphoma. In fact two labelled anti-CD20 antibodies, Zevalin (90Yt) and Bexxar (131I) have been used in successful clinical trials and both have been approved by the US FDA for the treatment of lymphoma.
Recombinant technology has facilitated the production of antibody fragments to overcome problems of delivery of the relatively large antibody molecules to cancer cells, particularly in solid tumours. Such heterogeneity of labelled antibody uptake, as well as heterogeneity of expression of the tumour antigen being targeted, has had an impact on the choice of radioactive isotope used in radioimmunotherapy. Thus, with the use of β-emitting isotopes, the range of which provides potential for “cross-fire”, tumour cells that escape binding by the labelled antibody are still subject to cell kill by the radiation flux from labelled neighbours. However, all these strategies have had limited success in realising a widespread role for radioimmunotherapy to treat solid tumours. Nevertheless the efforts continue, in particular exploring the potential of radioimmunotherapy to treat small tumour deposits, or minimal residual disease, for which antibody delivery is less of a problem.
Whereas the radioimmunotherapy strategy involves the use of tumour-seeking antibodies incorporating a radioactive isotope, another approach is to combine the tumour-targeting feature of particular antibodies with a non-radioactive toxic moiety. The first examples of such immunoconjugates used bacterial toxins as the cytotoxic moiety. However, for various reasons these approaches have not proved successful in the clinic (Kreitman, 2001). By contrast, drug-immunoconjugates seem much more promising. In general, the nature of the cytotoxic moiety requires that the antibody-receptor complex is internalised, in contrast to radioimmunotherapy where the range of action of the radioactive isotope is generally such that internalisation is not necessary.
The potency of the cytotoxic moiety of the immunoconjugate strategy is an important feature because of the limited number of receptors per cell. This consideration was the basis for the early interest in bacterial toxins, which are extremely potent, requiring only a few molecules per cell for cell kill. Calicheamicin, a member of a very potent enediyene class of cytotoxic drugs, has been conjugated to an anti-CD33 antibody. This conjugate, denoted Gemtuzumab Ozogamicin was recently approved by US FDA for treatment of acute myeloid lymphoma (AML). A number of similar products are now in development.
More recently U.S. Pat. No. 5,759,514 to Mattes has disclosed therapeutic anti-tumour conjugates of a DNA intercalating small molecule linked to an Auger electron-emitting radioisotope and a cell-targeting protein or polypeptide. This document, however, provides only limited information in relation to production of the conjugates and provides no demonstration that the conjugates are taken up by, and can give rise to selective elimination of, the target cells.
In view of the above discussion it is clear that further therapeutic approaches are required, which offer the capability of selectively targeting and eliminating specific cell populations, and tumour cell populations in particular. It is with this in mind that the present invention has been conceived. Furthermore, the present inventors have not only demonstrated that this invention provides a means of selectively eliminating target cells by virtue of Auger electron induced DNA strand breakage, but they have shown that the invention offers a means of imaging to assess the efficacy of delivery of the Auger-emitting isotope to the tumour, by gamma- and/or positron-emission. The information from such imaging could be used for dosimetry calculations for subsequent treatments. The inventors have also demonstrated the targeting of an alternative cytotoxic modality, namely by initiating photocleavage events in close proximity to target cell DNA, a strategy which has potential in ex-vivo purging of target cells and in selective target cell imaging.